Disconnect Between Skin Cells Implicated In Common Skin Cancer

Date:

February 23, 2001

Source:

University Of Chicago Medical Center

Summary:

A mutation that prevents skin cells from making normal connections with each other plays an unexpectedly early and important role in the development of the skin cancer, suggests a study published in the February 23, 2001 issue of Cell.

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A mutation that prevents skin cells from making normal connections with each other plays an unexpectedly early and important role in the development of the skin cancer, suggests a study published in the February 23, 2001 issue of Cell.

By altering one molecule in a skin cell-cell junction in mice researchers at the University of Chicago profoundly changed the skin and caused it to behave like a pre-cancerous condition called squamous cell carcinoma in situ. Squamous cell carcinoma is one of the two most common forms of skin cancer with more than one million cases reported in the United States each year.

"Although mutations of this molecule have been found in some types of cancer, it has generally been assumed that this was a late event following other mutations disrupting cell-cycle control," said Elaine Fuchs, Ph.D., Amgen Professor of Molecular Genetics and Cell Biology and a Howard Hughes Investigator at the University of Chicago, and lead investigator of the study.

"We discovered surprisingly, this component's loss appears to be a critical early event in the development of skin cancer," said Fuchs. "This molecule appears to be doing more than simply participating in cell-cell junctions."

The organization the skin's epidermal layer depends on cell-cell connections formed by two types of intercellular structures: adherens junctions and desmosomes. The molecule alpha-catenin plays a role in adherens junctions and connects these junctions to a dynamic structural framework in the cell, the actin cytoskeleton.

Their strategy was to breed a mouse that has had the gene for alpha-catenin removed, or knocked-out, selectively in skin cells. The mouse embryo developed normally until its skin and hair begin to develop, around the 14th day of gestation. As these specialized cells, called keratinocytes, developed they did not make adherens junctions. The alpha-catenin needed to anchor the junction was missing.

Changes in the skin of the knockout mouse were dramatic and largely unexpected. The epidermis was thick and disorganized. The characteristic cell shapes of each of the skin's four layers were distorted, making it hard to tell where one layer ended and another began. The knockout keratinocytes of the skin showed a number of aberrant signs frequently associated with cancers.

"Loss of alpha-catenin alone seemed to cause at least a partial deregulation of cell-cycle control," said Fuchs. "While one normally sees dividing cells only in the innermost layer, we saw them in multiple cell layers, including the ones near the skin surface that are normally in the process of dying. Cells often had more than one nucleus, an indication of defects in cell division."

Many of the defects in the skin of these mice did not seem to be merely a consequence of defective intercellular adhesion. To demonstrate this, the researchers looked at skin in a mouse in which the molecule with the same ascribed function in the desmosome cell junction was missing. Though both animals showed severe defects in adhesion, the skin in the desmosome knockout did not show the changes in cell cycle control.

When keratinocytes from the alpha-catenin knock-out mice were grown in cell-culture, the cells proliferated more rapidly than their normal counterparts, and kept dividing, causing them to pile up on top of each other.

Even when the cells were grown under conditions where cell-cell junction formation was blocked in normal skin cells, the alpha-catenin knock-out skin cells still displayed many of the characteristics of pre-cancerous cells. These studies suggested that the loss of alpha-catenin resulted in defects in cell cycle control that could not merely be explained by alpha-catenin's role in intercellular adhesion. In search of this additional pathway, Valera Vasioukhin, a postdoctoral fellow in Fuchs' group, discovered that the alpha-catenin knockout cells had aberrantly activated the Ras-MAPK signaling pathway that controls cell growth, and which is deregulated in many cancers. Exactly how this happens is still not clear, but their studies indicate that the signaling pathway of a cell that responds to growth factors intersects the pathway that regulates intercellular junction formation. At the crossroads of this junction appears to be alpha-catenin.

Skin cells respond to changes in their immediate environment. When their bonds with their neighboring cells are broken through wounding, for example, they begin to proliferate (grow and divide) to repair the wound. During this process, the cells must keep the number of intercellular contacts to a minimum so that they are free to move in to the wound site.

"Alpha-catenin may be acting as a sensor--communicating changes in cell adhesion to the cell cycle regulatory machinery. This could account for why mutations of alpha-catenin can perturb the normal regulation of cell growth," said Fuchs.

"Taken together, our findings reveal a novel, hitherto unrecognized, importance of this protein that goes beyond its role in intercellular adhesion and which when dysfunctional, may play a key role in this form of skin cancer. "

Elaine Fuchs , Ph.D., is Amgen Professor of Molecular Genetics and Cell Biology and a Howard Hughes Investigator at the University of Chicago.

Additional authors of the paper include Valera Vasioukhin, Ph.D., Christoph Bauer, Ph.D., Linda Degenstein, and Bart Wise, Ph.D., of the University of Chicago.

University Of Chicago Medical Center. "Disconnect Between Skin Cells Implicated In Common Skin Cancer." ScienceDaily. ScienceDaily, 23 February 2001. <www.sciencedaily.com/releases/2001/02/010223080145.htm>.

University Of Chicago Medical Center. (2001, February 23). Disconnect Between Skin Cells Implicated In Common Skin Cancer. ScienceDaily. Retrieved August 2, 2015 from www.sciencedaily.com/releases/2001/02/010223080145.htm

University Of Chicago Medical Center. "Disconnect Between Skin Cells Implicated In Common Skin Cancer." ScienceDaily. www.sciencedaily.com/releases/2001/02/010223080145.htm (accessed August 2, 2015).

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